Even in the current era of HAART, the central nervous system remains a target for viral infection and disease-induced damage in HIV-infected individuals. HIV is known to infect and persist in the brain in cells of the monocytic lineage. We have recently identified co-expression of the enzyme indoleamine 2,3- dioxygenase (IDO) with SIV in the brains of monkeys with SIV encephalitis, and have found IDO induction in microglia and macrophages in brains at both early and late stages of disease. IDO catalyzes the oxidative breakdown of tryptophan, and this reaction leads to a number of effects on both the immune and nervous system with important implications for HIV neuropathogenesis. We hypothesize that the expression of IDO in virus-infected macrophage creates a safe haven for the virus in the CNS, allowing persistence and spread of the infection. In the three proposed specific aims, we will examine the basis for the induction of IDO in infected cells, assess the factors that modulate IDO expression, and perform functional studies to uncover how this safe haven is created. In these studies, will investigate three hypotheses: 1) SIV infection of macrophages leads to IDO induction and sensitizes the cells to produce IDO at low levels of other stimulating agents; 2) SIV and the local environment influence the production and activity of IDO through specific transcriptional and post- transcriptional mechanisms; and 3) IDO alters the ability of host T cells to inhibit viral replication, with compensatory mechanisms protecting macrophage viability and viral production. These studies will uncover the molecular mechanisms by which IDO is regulated in microglia and macrophages, the means by which it contributes to neuropathogenesis in HIV infection, and lead to discoveries allowing such pathways to be manipulated therapeutically.